RESUMO
Although the consumption of carbohydrates is needed for survival, their potent reinforcing properties drive obesity worldwide. In turn, sugar overconsumption reveals a major role for brain reward systems in regulating sugar intake. However, it remains elusive how different cell types within the reward circuitries control the initiation and termination of sugary meals. Here, we identified the distinct nucleus accumbens cell types that mediate the chemosensory versus postprandial properties of sweet sugars. Specifically, D1 neurons enhance sugar intake via specialized connections to taste ganglia, whereas D2 neurons mediate the termination of sugary meals via anatomical connections to circuits involved in appetite suppression. Consistently, D2, but not D1, neurons partially mediate the satiating effects of glucagon-like peptide 1 (GLP-1) agonists. Thus, these nucleus accumbens cell types function as a behavioral switch, enabling positive versus negative control over sugar intake. Our study contributes to unveiling the cellular and circuit substrates of sugar overconsumption.
Assuntos
Neurônios , Núcleo Accumbens , Camundongos , Animais , Núcleo Accumbens/metabolismo , Neurônios/metabolismo , Encéfalo/metabolismo , Açúcares/metabolismo , Receptores de Dopamina D1/metabolismoRESUMO
Skin secretion of Hypsiboas punctatus is the source of a complex mixture of bioactive compounds where peptides and small proteins prevail, similarly to many other amphibians. Among dozens of molecules isolated from H. punctatus in a proteomic based approach, we report here the structural and functional studies of a novel peptide named Phenylseptin (FFFDTLKNLAGKVIGALT-NH2) that was purified as two naturally occurring D- and L-Phes configurations. The amino acid epimerization and C-terminal amidation for both molecules were confirmed by a combination of techniques including reverse-phase UFLC, ion mobility mass spectrometry, high resolution MS/MS experiments, Edman degradation, cDNA sequencing and solid-phase peptide synthesis. RMSD analysis of the twenty lowest-energy (1)H NMR structures of each peptide revealed a major 90° difference between the two backbones at the first four N-terminal residues and substantial orientation changes of their respective side chains. These structural divergences were considered to be the primary cause of the in vitro quantitative differences in antimicrobial activities between the two molecules. Finally, both molecules elicited equally aversive reactions in mice when delivered orally, an effect that depended entirely on peripheral gustatory pathways.